Gene Expression and Autoantibody Analysis Revealing Distinct Ancestry‐Specific Profiles Associated With Response to Rituximab in Refractory Systemic Lupus Erythematosus

Abstract

Objective. Gene expression profiles are associated with the clinical heterogeneity of systemic lupus erythematosus (SLE) but are not well studied as biomarkers for therapy. We studied gene expression and response to rituximab in a multiethnic UK cohort who were refractory to standard therapy.Methods. We evaluated baseline expression levels of transcripts known to associate with clinical features of SLE using a 96-probe TaqMan array and whole blood samples from 213 patients with active SLE who had been prospectively enrolled in the British Isles Lupus Assessment Group (BILAG) Biologics Register. We measured autoantibodies using immunoprecipitation and enzyme-linked immunosorbent assays. We determined responses to first-cycle rituximab at 6 months from treatment start in 110 SLE patients by assessing BILAG 2004 disease activity.Results. Interferon gene expression scores were lower in patients of European ancestry than in all other ancestry groups. The relationship between blood interferon gene expression scores and scores annotated to plasmablasts, neutrophils, myeloid lineage, inflammation, and erythropoiesis differed between patients of European and non-European ancestries. Hierarchical clustering revealed 3 distinct non-European ancestry patient subsets with stratified responses to rituximab that were not explained by sociodemographic and clinical variables, with responses lowest in an interferon-low, neutrophil-high cluster and highest in a cluster with high expression levels across all signatures (P < 0.001). Clusters in European ancestry patients did not predict response to rituximab but segregated patients by global disease activity and renal involvement. In both ancestral groups, interferon-high clusters were associated with U1 RNP/Sm antibodies.Conclusion. Ancestry appears central to the immunologic and clinical heterogeneity in SLE. These results suggest that ancestry, disease activity, and transcriptional signatures could each assist in predicting the effectiveness of B cell depletion therapies.

Blood RNA-sequencing across the continuum of ANA-positive autoimmunity reveals insights into initiating immunopathology

“…We adopted 12-month follow-up as endpoint for progression status and while total follow-up now extends to 3 years,8 we cannot exclude the possibility of later progression in some individuals, or other confounding latent pathologies. While demographic profiles were similar between ANA+ groups, subjects were not ancestry matched and diverging immune pathology between ethnic groups is increasingly recognised 30 39 40. Our work nevertheless identified novel areas for focused research in SLE pathogenesis.…”

Prevalence of concomitant rheumatologic diseases and autoantibody specificities among racial and ethnic groups in SLE patients

“…Recent studies have linked genetic ancestry to the heterogeneous gene expression and immunologic profiles in SLE. Our population level data may help inform future research in this area ( 52 , 53 ). In addition, by better understanding how autoantibody profiles differ in racial/ethnic groups, we can more appropriately incorporate our patients’ serologic data in their clinical context.…”

Role of IFN-α in Rheumatoid Arthritis

“…Despite mechanistic uncertainties, there is clear rationale to further test IFN-α targeting therapies in early RA, potentially using the IGS as a theragnostic biomarker, or to use the IGS as a biomarker for more intensive initial therapy. The heterogeneity and variety of IGSs remain challenging with regard to clinical utility, but recent progress in the international community on IGS stratification and uniform application of standardised measures of IFN-I signalling is encouraging [ 4 ••, 5 ••, 124 , 125 ], and its use in this capacity may be on the horizon.

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